Friday, 3 June 2016

Dysbiosis and D-lactate

Lactate (C3H6O3)
is an intermediate of carbohydrate metabolism, produced from pyruvate during
lactic acid fermentation. Lactate can exist as two enantiomers/stereoisomers,
L- and D-lactate, with L-lactate being the main form present in the body. Human
cells produce L-lactate from glucose and alanine, while a small amount of D-lactate
can be produced via the methylglyoxal pathway 1. However gut microbes can
produce both L- and/or D-lactate as major metabolic by-products 2.

Elevated gut
and/or blood levels of D-lactate are seen in several conditions and may be
harmful 1–3. An overgrowth of D-lactate-producing
gut bacteria has also been implicated in ME/CFS 4–6; although blood levels and
biological interactions/associations have not yet been investigated, making the
relevance unclear. Still, I think we can learn something from general research on
D-lactate production by the gut microbiota.

In the gut, dietary
carbohydrates provide fuel for microbial fermentation. Normally this should occur
predominantly in the colon, where indigestible carbs accumulate and are slowly broken
down into sugars. Many gut microbes (e.g. Lactobacilli,
Streptococci, Bifidobacteria, etc.) can subsequently perform lactic acid
fermentation and release lactate as metabolic waste 7. Some microbes express
D-lactic acid dehydrogenase (DDH) allowing them to produce D-lactate 2. Gut lactate levels normally remain
extremely low or undetectable, since both L- and D-lactate are intermediate substrates
for the production of SCFAs (mainly butyrate) 8–10, the normal end-products of
carbohydrate fermentation. However, large amounts of indigestible sugars (e.g.
lactulose 10 or FOS 11) have been shown to increase
colonic lactate levels in healthy individuals, likely due to production
outpacing utilisation.

In many
diseases there may be highly abnormal patterns of carbohydrate fermentation. This
may involve excessive fermentation in the small intestine (e.g. SIBO) or
dysregulated fermentation in the large intestine (colonic dysbiosis). Several gut
conditions (e.g. IBD, intestinal ischemia and short bowel) have been associated
with elevated colonic lactate and blood D-lactate levels, as a result of changes
to the intestinal environment (substrate availability, pH, blood flow, etc.) and
bacterial abundance 3.

Humans have some
ability to metabolise D-lactate via DDH/D-2-HDH (highest expression in liver
and kidneys) 1,2,12. However, at high production
rates, D-lactate can accumulate in blood. D-lactate may exert toxic effects. D-lactate
can directly interfere with pyruvate/lactate metabolism and mitochondrial
function in brain and heart tissue 12. If levels get high enough (>3
mmol/L) this can cause D-lactic acidosis, which is associated with an array of neurological
symptoms (e.g. encephalopathy, slurred speech, ataxia, etc.) 2. Notably, blood D-lactate
levels may only poorly correlate with neurological symptoms, suggesting other
factors are also involved 2.

D-lactic
acidosis typically occurs as a rare complication of short bowel syndrome. Here,
a shortened small intestine enables dietary sugars to reach the colon, where
they are rapidly fermented, resulting in a bloom of bacteria (i.e. Lactobacilli) which produce lactate, overwhelming
its utilisation 2. In these cases, meals high
in carbohydrates can promote acidosis. Therefore restriction of dietary
carbohydrate is important for management 2. Interestingly however, the
type of dietary carbohydrate also seems crucial. A couple of detailed case
reports, on people with short bowel and recurrent episodes of D-lactic
acidosis, have assessed the ability of their bacteria to produce D-lactate in
response to different carbohydrates 10,13. They found that simple
sugars (e.g. glucose, lactose, maltose, sucrose, etc.) promote D-lactate
production, whereas long-chain starch polysaccharides did not. Therefore
manipulation of dietary carbs to be low in sugars and high in starch eliminated
episodes of D-lactic acidosis 10,13. This may be because D-lactate-producing
bacteria cannot effectively break down starch, or just that simple sugars can
be metabolised far more rapidly 2. Also of interest, another
short bowel patient with recurrent D-lactic acidosis, was apparently
successfully treated long-term with a standalone synbiotic therapy, consisting
of probiotic bacteria and the prebiotic fibre GOS 14. In humans GOS mainly
supports the growth of Bifidobacteria15, which can alter fermentation
patterns and lower D-lactate levels in
vitro16.

Back to ME/CFS.
There is evidence of SIBO 17,18 and dysbiosis, including an overgrowth
of D-lactate producing bacteria (e.g. Streptococci
and Enterococci) 4. Levels of several lactic
acid bacteria also correlate with symptoms 5,6. However there is still no measurement
of gut microbiota DDH expression or gut and blood D-lactate. Also, if D-lactate
is an issue, then is carbohydrate type important? Notably, the D-lactate-producing
ability of bacteria elevated in ME/CFS was only tested with glucose 4, which at least implicates
sugars. However, since simple sugars are normally absorbed high up the
intestine, for them to be an issue implies malabsorption and/or SIBO.

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